There is a general lack of effective, inexpensive chemotherapeutic agents for the treatment of parasitic protozoal diseases that occur in the developing world. These parasitic protozoal diseases include leishmaniasis, including visceral leishmaniasis, mucocutaneous leishmaniasis, and cutaneous leishmaniasis; Chagas disease; human African trypanosomiasis, also known as African sleeping sickness; animal trypanosomiasis; and malaria.
Leishmaniasis currently threatens 350 million men, women and children in 88 countries around the world. The leishmaniases are parasitic diseases with a wide range of clinical symptoms: cutaneous, mucocutaneous and visceral. Visceral leishmaniasis—also known as kala azar is characterized by irregular bouts of fever, substantial weight loss, swelling of the spleen and liver, and anemia (occasionally serious). If left untreated, the fatality rate can be as high as 100%. In mucocutaneous forms of leishmaniasis, lesions can lead to partial or total destruction of the mucose membranes of the nose, mouth and throat cavities and surrounding tissues. These disabling and degrading forms of leishmaniasis can result in victims being humiliated and cast out from society. Cutaneous forms of the disease normally produce skin ulcers on the exposed parts of the body such as the face, arms and legs. The disease can produce a large number of lesions—sometimes up to 200—causing serious disability and invariably leaving the patient permanently scarred, a stigma which can cause serious social prejudice.
The leishmaniases are caused by different species belonging to the genus Leishmania a protozoa transmitted by the bite of a tiny 2 to 3 millimeter-long insect vector, the phlebotomine sandfly. Of 500 known phlebotomine species, only some 30 of them have been positively identified as vectors of the disease. Only the female sandfly transmits the protozoan, infecting itself with the Leishmania parasites contained in the blood it sucks from its human or mammalian host in order to obtain the protein necessary to develop its eggs. During a period of 4 to 25 days, the parasite continues its development inside the sandfly where it undergoes major transformation. When the now infectious female sandfly feeds on a fresh source of blood, its painful sting inoculates its new victim with the parasite, and the transmission cycle is completed.
The insect vector of leishmaniasis, the phlebotomine sandfly, is found throughout the world's inter-tropical and temperate regions. The female sandfly lays its eggs in the burrows of certain rodents, in the bark of old trees, in ruined buildings, in cracks in house walls, and in household rubbish, as it is in such environments that the larvae will find the organic matter, heat and humidity which are necessary to their development. In its search for blood (usually in the evening and at night), the female sandfly covers a radius of a few meters to several hundreds around its habitat. For a long time, little was known about the transmission cycles of the disease, but over the last few years, field research and the application of molecular biology have enabled substantial progress to be made in understanding the different links in the transmission chain. Moreover, simple new diagnostic techniques have recently been developed which are practical, reliable and inexpensive. These techniques are available to concerned countries for the early detection and rapid treatment of the disease.
The Leishmaniases are related to environmental changes such as deforestation, building of dams, new irrigation schemes, urbanization and migration of non-immune people to endemic areas. It seriously hampers productivity and vitally needed socioeconomic progress and epidemics have significantly delayed the implementation of numerous development programs. This is particularly true in Saudi Arabia, Morocco, the Amazon basin and the tropical regions of the Andean countries.
For many years, the public health impact of the leishmaniases has been grossly underestimated, mainly due to lack of awareness of its serious impact on health. Over the last 10 years endemic regions have been spreading further afield and there has been a sharp increase in the number of recorded cases of the disease. As declaration is obligatory in only 32 of the 88 countries affected by leishmaniasis, a substantial number of cases are never recorder. In fact, of the 1.5–2 million new cases estimated to occur annually, only 600,000 are officially declared
In addition, deadly epidemics of visceral leishmaniasis periodically flare up. For example, in the 1990s Sudan suffered a crisis with an excess mortality of 100,000 deaths among people at risk. An epidemic of cutaneous leishmaniasis is ongoing in Kabul, Afghanistan with an estimated 200,000 cases.
Chagas disease has a wide distribution in Central and South America, being found only in the American Hemisphere. It is endemic in 21 countries, with 16–18 million persons infected and 100 million people at risk. The disease is caused by Trypanosoma cruzi, a flagellated protozoan parasite which is transmitted to humans in two ways, either by a blood-sucking reduviid bug which deposits its infective feces on the skin at the time of biting, or directly by transfusion of infected blood. Humans and a large number of species of domestic and wild animals constitute the reservoir, and the vector bugs infest poor housing and thatched roofs.
The acute stage of the disease is generally seen in children, and is characterized by fever, swelling of lymph glands, enlargement of the liver and spleen, or local inflammation at the site of infection. But, commonly, there are no acute clinical manifestations, and those infected may remain without symptoms. In about one-third of acute cases, a chronic form develops some 10–20 years later, causing irreversible damage to the heart, esophagus and colon, with dilatation and disorders of nerve conduction of these organs. Patients with severe chronic disease become progressively more ill and ultimately die, usually from heart failure. There is, at present, no effective treatment for such cases.
Rural migrations to urban areas during the 1970s and 1980s changed the traditional epidemiological pattern of Chagas disease: it became an urban disease, as unscreened blood transfusion created a second way of transmission. Between 1960 and 1989, the prevalence of infected blood in blood banks in selected cities of South America ranged from 1.7% in Sao Paulo, Brazil to 53.0% in Santa Cruz, Bolivia, a percentage far higher than that of hepatitis or HIV infection.
Human African trypanosomiasis, known as sleeping sickness, is a vector-borne parasitic disease. Trypanosoma, the parasites concerned, are protozoa transmitted to humans by tsetse flies (glossina). Tsetse flies live in Africa, and they are found in vegetation by rivers and lakes, gallery-forests and vast stretches of wooded savannah. Sleeping sickness occurs only in sub-Saharan Africa, in regions where tsetse flies are endemic. For reasons as yet unknown, there are many regions where tsetse flies are found, but sleeping sickness is not. The rural populations that live in such environments and depend on them for agriculture, fishing, animal husbandry or hunting are the most exposed—along with their livestock—to the bite of the tsetse fly.
Sleeping sickness affects remote and rural areas where health systems are least effective, or non-existent. It spreads with socio-economic problems such as political instability, displacement of populations, war and poverty. It develops in foci whose size can range from a village to an entire region. Within a given focus, the intensity of the disease can vary considerably from one village to the next.
Human African trypanosomiasis takes two forms, depending on the parasite involved: Trypanosoma brucei gambiense (T.b. gambiense) is found in central and West Africa. It causes chronic infection, which does not mean benign. A person can be infected for months or even years without obvious symptoms of the disease emerging. When symptoms do emerge, the disease is already at an advanced stage. Trypanosoma brucei rhodesiense (T.b. rhodesiense) is found in southern and east Africa. It causes acute infection that emerges after a few weeks. It is more virulent than the other strain and develops more rapidly, which means that it is more quickly detected clinically.
Other sub-species of the parasite cause animal trypanosomiasis, which are pathogenic to animals and are often different from those that cause the disease in humans. Animals can carry parasites, especially T.b. rhodesiense; domestic and wild animals are a major reservoir. They can also be infected with T.b. gambiense, though the precise role of this reservoir is not well known. The two human and animal forms of the disease remain a major obstacle to the development of rural regions of sub-Saharan Africa: human loss, decimation of cattle and abandonment of fertile land where the disease is rife.
There have been three severe epidemics in Africa over the last century: one between 1896 and 1906, mostly in Uganda and the Congo Basin, one in 1920 in several African countries, and one that began in 1970 and is still in progress. The 1920 epidemic was arrested due to mobile teams systematically screening millions of people at risk. The disease had practically disappeared between 1960 and 1965. After that success, screening and effective surveillance were relaxed, and the disease has reappeared in endemic form in several foci over the last thirty years.
Sleeping sickness threatens over 60 million people in 36 countries of sub-Saharan Africa. Only 3 to 4 million people at risk are under surveillance, with regular examination or access to a health centre that can provide screening. Detection of the disease calls for major human and material resources, such as well-equipped health centers and qualified staff. Because such resources are lacking, most people with sleeping sickness die before they can ever be diagnosed. Almost 45,000 cases were reported in 1999, but the World Health Organization (WHO) estimates that the number of people affected is ten times greater. The 45,000 case figure shows not the true situation but rather the lack of screening in many foci. The real number of cases seems to be between 300,000 and 500,000. Reported cases in recent years are from countries where surveillance coverage is no more than 5%.
In certain villages of many provinces of Angola, the Democratic Republic of Congo and southern Sudan, the prevalence is between 20% and 50%. Sleeping sickness has become the first or second greatest cause of mortality, ahead of HIV/AIDS, in those provinces.
Countries are placed in four categories in terms of prevalence. In each country the spatial distribution of the disease is very diverse; it is found in foci and micro-foci. Countries where there is an epidemic of the disease, in terms of very high cumulated prevalence and high transmission: Angola, Democratic Republic of Congo and Sudan. Highly endemic countries, where prevalence is moderate but increase is certain: Cameroon, Central African Republic, Chad, Congo, Côte d'Ivoire, Guinea, Mozambique, Uganda and United Republic of Tanzania. Countries where the endemic level is low: Benin, Burkina Faso, Equatorial Guinea, Gabon, Kenya, Mali, Togo and Zambia. Countries whose present status is not clear: Botswana, Burundi, Ethiopia, Liberia, Namibia, Nigeria, Rwanda, Senegal and Sierra-Leone.
The disease is transmitted with the bite of the tsetse fly. At first the trypanosomes multiply in the blood, and that process can last for years with T.b. gambiense. Mother-to-child infection: the trypanosome can cross the placenta and infect the fetus, causing abortion and perinatal death. Accidental infections can occur in laboratories, for example, through the handling of blood of an infected person, although this is fairly rare. The early phase entails bouts of fever, headaches, pains in the joints and itching. The second, known as the neurological phase, begins when the parasite crosses the blood-brain barrier and infests the central nervous system. This is when the characteristic signs and symptoms of the disease appear: confusion, sensory disturbances and poor coordination. Disturbance of the sleep cycle, which gives the disease its name, is the most important feature. Without treatment, the disease is fatal. If the patient does not receive treatment before the onset of the second phase, neurological damage is irreversible even after treatment.
There are three stages to case management: Screening is the initial sorting of people who might be infected. This involves checking for clinical signs or the use of serological tests. Diagnosis shows whether the parasite is present. The only sign, one that has been known for centuries, is swollen cervical glands. Phase diagnosis shows the state of progression of the disease. It entails examination of cerebro-spinal fluid obtained by lumbar puncture and is used to determine the course of treatment. The long, asymptomatic first phase of T.b. gambiense sleeping sickness is one of the factors that makes treatment difficult. Diagnosis must be made as early as possible in order to preclude the onset of irreversible neurological disorders and prevent transmission. Case detection is difficult and requires major human, technical and material resources. Since the disease is rife in rural areas among poor people with little access to health facilities, this problem is all the more difficult.
If the disease is diagnosed early, the chances of cure are high, but early diagnosis of the disease, which would guarantee low-risk treatment on an outpatient basis, can rarely be achieved. The type of treatment depends on the phase of the disease: initial or neurological. Success in the latter phase depends on having a drug that can cross the blood-brain barrier to reach the parasite. Four drugs have been used until now. However drugs are old, difficult to administer in poor conditions and by no means always successful.
Malaria is a life-threatening parasitic disease transmitted by mosquitoes. Today approximately 40% of the world's population—mostly those living in the world's poorest countries—is at risk of malaria. The disease was once more widespread but it was successfully eliminated from many countries with temperate climates during the mid 20th century. Today malaria is found throughout the tropical and sub-tropical regions of the world and causes more than 300 million acute illnesses and at least one million deaths annually. Ninety per cent of deaths due to malaria occur in Africa, south of the Sahara—mostly among young children. Malaria kills an African child every 30 seconds. Many children who survive an episode of severe malaria may suffer from learning impairments or brain damage. Pregnant women and their unborn children are also particularly vulnerable to malaria, which is a major cause of perinatal mortality, low birth weight and maternal anemia.
Malaria parasites have become resistant to one drug after another and many insecticides are no longer useful against the mosquitoes which transmit the disease. Years of vaccine research have produced few hopeful candidates.
Because of the general lack of effective, inexpensive chemotherapeutic agents for treating parasitic protozoal diseases that occur in the developing world, new chemotherapeutic agents are needed. For example, it is estimated that approximately 1.5–2 million new cases of leishmaniasis occur each year due to infection by various Leishmania species.1 Pentavalent antimonial drugs are the first line treatment for leishmaniasis in most affected areas, with amphotericin B and pentamidine being used as alternatives.2 These agents must be administered by injection over several days to weeks, increasing the cost and inconvenience of the drugs. Resistance to antimonials has become a severe problem,3 and treatment with amphotericin B and pentamidine is frequently complicated by the occurrence of toxic side effects.2 Clearly, improved chemotherapeutics are needed against this disease, as well as the other parasitic diseases.